One-Pot Synthesis of Polysubstituted Imidazoles via Sequential Staudinger/aza-Wittig/Ag(I)-Catalyzed Cyclization/Isomerization

Article abstract of DOI:10.1021/acs.joc.7b02606

A new one-pot preparation of polysubstituted imidazoles by a Staudinger/aza-Wittig/Ag(I)-catalyzed cyclization/isomerization has been developed. The easily accessible propargylazide derivatives reacted with triphenylphosphine, isocyanates, and amines sequ

Full text of DOI:10.1021/acs.joc.7b02606

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Note
One-Pot Synthesis of Polysubstituted Imidazoles via Sequential
Staudinger/aza-Wittig/Ag(I)-Catalyzed Cyclization/Isomerization
Jun Xiong, Xiao Wei, Zi-Ming Liu, and Ming-Wu Ding
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02606 • Publication Date (Web): 17 Nov 2017
Downloaded from http://pubs.acs.org on November 17, 2017
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One-Pot Synthesis of Polysubstituted Imidazoles via Sequential
Staudinger/aza-Wittig/Ag(I)-Catalyzed Cyclization/Isomerization
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Jun Xiong, Xiao Wei, ZiꢀMing Liu and MingꢀWu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal
University, Wuhan 430079, P. R. China
Eꢀmail: mwding@mail.ccnu.edu.cn
1. PPh3
2. R2NCO
3. HNR3R4
R2
N
Ar
NR3R4
Ar
4. AgNO3(10%)
DMAP(10%)
one pot
N3
N
R1
R1
ABSTRACT:
A
new
oneꢀpot
preparation
of
polysubstituted
imidazoles
by
a
Staudinger/azaꢀWittig/Ag(I)ꢀcatalyzed cyclization/isomerization has been developed. The easily acessible
propargylazide derivatives reacted with triphenylphosphine, isocyanates and amines sequentially to
produce the fully substituted imidazoles in good overall yields in the presence of catalytic amount of
AgNO3/DMAP.
Key words: silver catalysis; imidazole; Staudinger reaction; azaꢀWittig reaction; azide
Polysubstituted imidozoles are important heterocycles due to their remarkable biological and
pharmaceutical activities, which have been found in various nature products and artificial drugs (Figure
1).1 A wide varity of derivatives of this ring system have recently been used as Janusꢀassociated kinase 2
(Jak2) inhibitors,2 Takeda Gꢀproteinꢀcoupled receptor 5 (TGR5) agonists,3 antiviral agents,4 antimicrobial
agents,5 antiꢀAlzheimer's disease agents,6 and particularly anticancer agents.7 In addition, imidazole rings
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were also found application in coordination chemistry, or be used as organic catalysts.8 In the past few
years, many new methods for synthesis of imidazole have been reported,9ꢀ17 including Ag, Rh, Fe,
Cuꢀcatalyzed reactions, or other metalꢀfree cyclizations. For examples, some 1,2,4ꢀtrisubstituted
imidazoles were efficiently prepared by silverꢀpromoted [3+2] cycloaddition of azomethine ylides with
isocyanides with broad substrate scope and good functional group compatibility.9 The sequential reaction
of allenyl sulfonamides and amines was successfully utilized in regioselective synthesis of highly
substituted imidazoles.10 A new, oneꢀpot synthesis of imidazoles was also provided by reaction of imines,
acid chlorides, and Nꢀnosyl imines or tethered nitriles, mediated by the phosphonite via regioselective
cycloaddition.11 Despite of their many advantages however, these methods suffer from some drawbacks
including harsh reaction condition, acidꢀ or baseꢀsensitive substrates, or multiꢀstep operation.
Consequently, new and direct synthetic method to imidazoles is still desirable in synthetic organic and
pharmaceutical chemistry.
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OMe
Cl
N
OH
N
N
N
N
F
N
NH
OMe
N
H
F
Losartan
(antihypertensive)
Fenflumizol
(anti-inflammatory)
F
Cl
F
N
Cl
N
N
N
HO
F
H
N
NH
OMe
H
O
N
Cl
anticancer
anti-Alzheimer's disease
Figure 1. Representative Drugs and Biologically Active Imidazoles
Intramolecular cyclization between alkynes and nitrogen nucleophiles is one of the most important
methods for the synthesis of Nꢀheterocycles.18 The reaction could be catalyzed by transition metal
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complexes, such as Pd, Au, Cu, In, Ag, etc.19 Recently, Ag(I) salts are found to be an efficient activator of
alkynes and they have received great attention in view of their lower activation energy to obtain target
compound in mild condition.20 For example, Van der Eycken disclosed a facile route to 2ꢀimidazolone via
a Ag(I)ꢀcatalyzed cycloisomerization reaction of secondary propargylamine with isocyanate.21 The
azaꢀWittig reaction of iminophosphoranes with carbonyl compounds has provided a powerful method for
the assembly of C=N double bond under mild and neutral conditions.22 It has recently used widely in the
synthesis of various heterocyclic compounds.23 The azaꢀWittig reactions of iminophosphoranes with
isocyanates produce high reactive carbodiimide intermediates, which may be utilized in preparing some
heterocycles in further sequential reactions.24 It was reported that 2ꢀamino imidazoles could be prepared
by such synthetic approach starting from 2ꢀethoxycarbonyl azides.25 However, the method included a
tedious multiꢀstep process involving a first azaꢀWittig reaction of 2ꢀethoxycarbonyl iminophosphorane to
give imidazolinꢀ5(4H)ꢀones, and then DIBAL reduction of imidazolinꢀ5(4H)ꢀones to
5ꢀhydroxydihydroimidazoles, afterward methanesulfonylation of the hydroxyl group and finally
elimination to give 2ꢀamino imidazoles. Continuing our interests in synthesis of heterocycles via
azaꢀWittig reactions,26 herein we wish to report a new efficient and oneꢀpot synthesis of
1,2,4,5ꢀtetrasubstituted imidazoles by Ag(I)ꢀcatalyzed intramolecular cyclization of αꢀalkynylguanidines,
which were obtained by azaꢀWittig reaction and further reaction of the carbodiimides with amines. Our
procedure gave a dexterous oneꢀpot synthesis of 2ꢀamino imidazoles with elaborate substitution patterns
from the easily accessible propargyl azides, superior to previous reports.
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The starting material propargylazides 3 were prepared as illustrated in Scheme 1. PdꢀCatalyzed
Sonogashina coupling reaction of aryl halides with commercial available propꢀ2ꢀynꢀ1ꢀols gave propargyl
alcohols 1.27 Mesylation of compounds 1 with methanesulfonyl chloride in the presence of triethylamine
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produces the mesylates 2, which were treated with sodium azide in DMF to generate the propargylazides
3.28
7
8
9
Scheme 1. Preparation of Propargylazide Derivatives 3
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Ar
ArI
MsCl/Et3N
CH2Cl2
R1
R1
Pd(PPh3)2Cl2
CuI
OH
OH
1
Ar
Ar
NaN3
DMF
R1
R1
N3
OMs
3
2
Initially, we selected (3ꢀazidopropꢀ1ꢀynꢀ1ꢀyl)benzene 3a as the starting material (Scheme 2). As azide
3a was treated with triphenylphosphine in CH3CN, iminophosphorane 4a was formed. Reaction of 4a
with phenyl isocyanate produced the carbodiimide 5a, which was allowed to react with piperidine to
generate the guanidine intermediate 6a. To optimize the reaction conditions, the cyclization of
intermediate 6a was chosen as a model reaction. When the reaction was performed in the presence of
AgNO3 (0.1 equiv), and DMAP (0.1 equiv) in CH3CN at 80 °C, imidazole 7a was directly obtained in
84% isolated yield (Table 1, Entry 3). However, in the absence of a catalyst or a base, no product 7a was
formed (Table 1, entry 1 and 2). Then we screened base, including tꢀBuOK, NaH, DBU and Et3N (Table 1,
entry 4ꢀ7), and found that DMAP was optimal. The suitable basicity of DMAP might be responsible for
the relative better yield. As the catalyst was changed to PdCl2 or CuI, low yields (21ꢀ26%) of the product
were resulted (Table 1, entry 8 and 9). In case that Pd(OAc)2 was utilized, 74% of the product 7a was
obtained (Table 1, entry 10). No product was detected when the reaction temperature was decreased to
room temperature in the presence of AgNO3/DMAP system (Table 1, entry 11). Therefore, the optimum
reaction condition was identified (Table 1, entry 3).
Scheme 2. Preparation of Compounds 7a
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Ph
Ph
Ph
PhNCO
Ph3P
5
6
7
8
9
CH3CN
N3
N
C
N
Ph
Ph
N
PPh3
3a
4a
5a
Ph
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NH
N
Ph
Catalyst
Base
NHPh
N
N
N
N
6a
7a
Table 1. Optimization of the Reaction Conditions
entry
1
Catalyst[a]
Base[b]
DMAP
None
Condition
80 °C /12 h
80 °C /12 h
80 °C /12 h
80°C /12 h
80 °C /12 h
80 °C /12 h
80 °C /12 h
80 °C /12 h
80 °C /12 h
80 °C /12 h
r.t. /48 h
Yield[c] (%)
None
0
AgNO3
2
0
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
PdCl2
3
DMAP
tꢀBuOk
NaH
84
75
53
72
70
26
21
74
0
4
5
6
DBU
7
Et3N
8
DMAP
DMAP
DMAP
DMAP
CuI
9
Pd(OAc)2
10
11
AgNO3
a 10%mol amount of the catalyst; b 10%mol amount of the base; c isolated yields.
With the optimized condition in hand, we started to examine the scope of the reaction (Scheme 3). As
indicated in Table 2, the yields of products were related to R2 and NR3R4 groups. As aromatic isocyanates
were used (R2 are aryl groups), the reaction produced desired products in good overall yields (69ꢀ89%,
Table 2, compounds 7aꢀ7p), however, moderate yields (59ꢀ62%, Table 2, compounds 7qꢀ7s) were
obtained in case that alkyl isocyanates were utilized probably due to their relative lower reactivity toward
iminophosphorane 4. In addition, the amino group NR3R4 is also an important influencing factor for the
yield of the reaction. When secondary amines and aromatic isocyanates were used as the reaction
components, satisfactory yields of the products (71ꢀ89%, Table 2, compounds 7aꢀ7i and 7n-7p) were
obtained. However, relative lower yields (69ꢀ72%, Table 2, compounds 7jꢀ7m) were obtained in case that
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primary amines were applied.
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7
Scheme 3. Preparation of Compounds 7
8
9
Ar
Ar
C
Ar
R2NCO
Ph3P
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R1
R1
CH3CN
R1
N3
N
N
R2
N
PPh3
3
4
5
Ar
Ar
R2
NR3R4
AgNO3
(10%)
R1
HNR3R4
N
R1
NHR2
N
DMAP
(10%)
N
NR3R4
6
7
Table 2. Preparation of Imidazoles 7a
Ar
R1
R2
NR3R4
Yield[a] (%)
7a
7b
Ph
Ph
H
H
Ph
piperidinꢀ1ꢀyl
Et2Nꢀ
84
82
78
82
72
81
82
86
89
72
4ꢀMeC6H4
4ꢀMeC6H4
3ꢀMeC6H4
4ꢀClC6H4
4ꢀClC6H4
4ꢀFC6H4
4ꢀMeC6H4
Ph
7c
7d
7e
7f
Ph
H
morpholinꢀ4ꢀyl
piperidinꢀ1ꢀyl
PhCH2(Me)Nꢀ
Pr2Nꢀ
Ph
H
H
H
Ph
4ꢀMeC6H4
4ꢀMeC6H4
4ꢀMeC6H4
4ꢀClC6H4
Ph
7g
7h
7i
H
PhCH2(Me)Nꢀ
pyrrolidinꢀ1ꢀyl
Pr2Nꢀ
H
H
H
H
PhCH2NHꢀ[b]
7j
2ꢀClC6H4
4ꢀCH3OC6H4 tꢀBuNHꢀ[b]
71
70
69
80
71
74
61
59
62
7k
7l
Ph
4ꢀMeC6H4
H
Ph
BuNHꢀ[b]
iꢀPrNHꢀ[b]
7m 4ꢀClC6H4
H
4ꢀMeC6H4
Ph
7n
7o
7p
7q
7r
7s
Ph
Me
Me
Et
H
Pr2Nꢀ
Ph
2ꢀClC6H4
4ꢀMeC6H4
Bu
piperidinꢀ1ꢀyl
Pr2Nꢀ
Ph
Ph
piperidinꢀ1ꢀyl
piperidinꢀ1ꢀyl
PhCH2(Me)Nꢀ
4ꢀMeC6H4
4ꢀClC6H4
H
iꢀPr
H
iꢀPr
a Isolated yields based on the propargylazide 3. b Primary amine was used.
A proposed mechanism for the oneꢀpot formation of the imidazoles 7 is presented in Scheme 4. The
triple bond of compound 6 coordinates firstly to the silver nitrate to give the intermediate 8. Then
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5ꢀexoꢀdig cyclization of 8 provides the vinylsilver species 9 in the presence of the base DMAP.
Subsequent proton transfer in intermediate 9 with loss of Ag(I) provides dihydroimidazole 10 bearing an
exocyclic double bond. Further isomerization of dihydroimidazole 10 through 1,3ꢀH shift takes place to
produce imidazole product 7.
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Scheme 4. Proposed Mechanism for the One-Pot Formation of Imidazoles 7
Ar
Ar
R2
R1
NHR2
Ar
R2
NR3R4
R1
N
R1
NR3R4
Ag+
N
N
N
N
6
NR3R4
10
7
Ar
Ag
Ag+
Ar
R2
R1
NH+
R1
NHR2
N
N
NR3R4
NR3R4
9
8
5-exo-dig cyclization
In summary, we have developed a new method for preparation of 1,2,4,5ꢀtetrasubstituted imidazoles by
sequential Staudinger/azaꢀWittig/Ag(I)ꢀcatalyzed cyclization/isomerization starting from the easily
accessible propargylazide derivatives. The method was adapted to the synthesis of various polysubstituted
imidazoles in oneꢀpot fashion under mild reaction condition, which makes it useful in synthetic and
medicinal chemistry.
Experimental Section
One-pot synthesis of imidazoles
7
via sequential Staudinger/aza-Wittig/Ag(I)-catalyzed
cyclization/isomerization. To a solution of azide 3 (2 mmol) in CH3CN (10 mL) was added PPh3 (0.52 g,
2 mmol), the mixture was stirred at room temperature for 1 h to form iminophosphorane 4 (TLC
monitoring). Then isocyanate (2 mmol) was added dropwise at 0 °C. After the reaction mixture was left to
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stand for 30 min, the amine (2 mmol) was added. The reaction mixture was stirred at room temperature
for 0.5 h (as R2 is an aryl group) or 80 °C for 12ꢀ24 h (as R2 is an alkyl group) to form guanidine 6. Then
AgNO3 (0.034 g, 0.2 mmol) and DMAP (0.024 g, 0.2 mmol) was added to the reaction system, and the
reaction mixture was heated to 80 °C for another 12ꢀ24 h to form 7. The solvent was removed under
reduced pressure and the residue was purified by column chromatography on silica gel (petroleum
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ether/ethyl acetate = 8:1ꢀ4:1, V/V) to give 7.
1-(5-Benzyl-1-phenyl-1H-imidazol-2-yl)piperidine (7a). Light yellow solid (yield 0.533 g, 84%), mp
1
103ꢀ104 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.37ꢀ7.13 (m, 7H), 6.97 (d, J = 7.8 Hz, 2H), 6.57 (s,
1H), 3.68 (s, 2H), 2.91 (t, J = 4.8 Hz, 4H), 1.41ꢀ1.36 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.3,
138.5, 136.8, 129.0, 128.7, 128.5, 128.1, 127.8, 127.4, 126.0, 123.2, 50.6, 31.3, 25.4, 24.0. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C21H24N3 318.1965; Found 318.1975.
1
5-Benzyl-N,N-diethyl-1-(p-tolyl)-1H-imidazol-2-amine (7b). Light yellow oil (yield 0.524 g, 82%); H
NMR (CDCl3, 600 MHz) δ (ppm) 7.20ꢀ7.14 (m, 5H), 6.99 (d, J = 7.2 Hz, 2H), 6.94 (d, J = 7.2 Hz, 2H),
6.60 (s, 1H), 3.64 (s, 2H), 2.93 (q, J = 7.2 Hz, 4H), 2.37 (s, 3H), 0.90 (t, J = 7.2 Hz, 6H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 152.0, 138.6, 137.8, 134.1, 129.5, 128.7, 128.5, 128.1, 127.6, 126.0, 123.2,
46.0, 31.2, 21.1, 12.8. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C21H26N3 320.2121; Found 320.2149.
4-(5-Benzyl-1-(p-tolyl)-1H-imidazol-2-yl)morpholine (7c). Light yellow solid (yield 0.520 g, 78%), mp
90ꢀ92 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.68ꢀ6.97 (m, 9H), 6.57 (s, 1H), 3.66 (s, 2H), 3.54 (t, J =
4.8 Hz, 4H), 2.96 (t, J = 4.8 Hz, 4H), 2.37 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.9, 138.3,
138.2, 133.6, 132.0, 129.8, 128.5, 128.1, 127.1, 126.1, 122.9, 66.5, 49.6, 31.1, 21.2. HRMS (ESIꢀTOF)
m/z: [M + H]+ Calcd for C21H24N3O 334.1914; Found 334.1917.
1-(5-Benzyl-1-(m-tolyl)-1H-imidazol-2-yl)piperidine (7d). Light yellow solid (yield 0.544 g, 82%), mp
74ꢀ75 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.26ꢀ6.96 (m, 8H), 6.88 (s, 1H), 6.56 (s, 1H), 3.67 (s, 2H),
2.91 (t, J = 4.8 Hz, 4H), 2.31 (s, 3H), 1.42ꢀ1.38 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.3,
138.9, 138.7, 136.8, 128.8, 128.7, 128.6, 128.5, 128.1, 128.0, 126.1, 124.3, 123.2, 50.6, 31.4, 25.5, 24.1,
21.2. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C22H26N3 332.2121; Found 332.2137.
N,5-Dibenzyl-1-(4-chlorophenyl)-N-methyl-1H-imidazol-2-amine (7e). Light yellow oil (yield 0.559 g,
72%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.31ꢀ7.15 (m, 8H), 7.00ꢀ6.95 (m, 6H), 6.66 (s, 1H), 4.02 (s,
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2H), 3.66 (s, 2H), 2.53 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.1, 138.1, 137.4, 135.0, 134.1,
129.3, 129.2, 128.9, 128.3, 128.2, 128.1, 128.0, 127.1, 126.2, 123.4, 58.4, 39.0, 31.1. HRMS (ESIꢀTOF)
m/z: [M + H]+ Calcd for C24H23ClN3 388.1575; Found 388.1596.
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1-(4-Chlorophenyl)-5-(4-methylbenzyl)-N,N-dipropyl-1H-imidazol-2-amine (7f). Light yellow oil (yield
0.619 g, 81%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.35 (d, J = 8.4 Hz, 2H), 7.02ꢀ6.98 (m, 4H), 6.84 (d,
J = 7.2 Hz, 2H), 6.64 (s, 1H), 3.57 (s, 2H), 2.86 (t, J = 7.2 Hz, 4H), 2.30 (s, 3H), 1.38ꢀ1.34 (m, 4H), 0.71
(t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 151.8, 135.8, 134.9, 134.7, 134.2, 129.3, 129.2,
128.9, 128.8, 128.7, 128.2, 53.7, 30.7, 20.9, 20.8, 11.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C23H28ClN3Na 404.1864; Found 404.1845.
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N-Benzyl-1-(4-fluorophenyl)-N-methyl-5-(4-methylbenzyl)-1H-imidazol-2-amine (7g). Light yellow oil
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(yield 0.632 g, 82%); H NMR (CDCl3, 600 MHz) δ (ppm) 7.21 (d, J = 7.8 Hz, 3H), 7.04ꢀ6.97 (m, 8H),
6.83 (d, J = 7.2 Hz, 2H), 6.66 (s, 1H), 4.05 (s, 2H,), 3.59 (s, 2H), 2.58 (s, 3H), 2.29 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 162.9, 161.3, 152.5, 137.2, 135.8, 134.7, 132.0, 129.8, 129.7, 129.4, 128.9,
128.2, 128.0, 127.2, 121.9, 116.2, 116.1, 58.2, 39.0, 30.7, 20.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C25H25FN3 386.2027; Found 386.2031.
5-(4-Methylbenzyl)-2-(pyrrolidin-1-yl)-1-(p-tolyl)-1H-imidazole (7h). Light yellow oil (yield 0.570 g,
86%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.13 (d, J = 7.2 Hz, 2H), 6.99 (t, J = 7.8 Hz, 4H), 6.88 (d, J =
7.8 Hz, 2H), 6.49 (s, 1H), 3.54 (s, 2H), 3.03 (t, J = 7.2 Hz, 4H), 2.38 (s, 3H), 2.29 (s, 3H), 1.73ꢀ1.71 (m,
4H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.1, 137.9, 135.7, 135.4, 134.4, 129.5, 128.7, 128.4, 128.3,
128.2, 122.4, 49.5, 30.7, 25.1, 21.1, 20.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C22H26N3 332.2121;
Found 332.2119.
5-(4-Chlorobenzyl)-1-phenyl-N,N-dipropyl-1H-imidazol-2-amine (7i). Light yellow oil (yield 0.655 g,
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89%); H NMR (CDCl3, 600 MHz) δ (ppm) 7.36ꢀ7.02 (m, 7H), 6.86 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H),
3.61 (s, 2H), 2.83 (t, J = 7.2 Hz, 4H), 1.35ꢀ1.30 (m, 4H), 0.68 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150
MHz) δ (ppm) 152.7, 137.0, 136.7, 131.7, 129.7, 128.9, 128.1, 128.0, 127.9, 127.8, 123.3, 53.7, 30.6, 20.8,
11.2. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C22H27ClN3 368.1888; Found 368.1873.
N,5-Dibenzyl-1-(2-chlorophenyl)-1H-imidazol-2-amine (7j). White solid (yield 0.538 g, 72%), mp 90ꢀ91
°C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.44 (d, J = 7.8 Hz, 1H), 7.34ꢀ7.11 (m, 10H), 7.00 (d, J = 7.8 Hz,
1H), 6.90 (d, J = 6.6 Hz, 2H), 6.64 (s, 1H), 4.57ꢀ4.48 (m, 2H), 3.69 (d, J = 16.2 Hz, 1H), 3.56ꢀ3.51 (m,
2H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 149.4, 139.2, 138.2, 133.7, 132.5, 130.8, 130.6, 130.5, 128.5,
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128.4, 128.0, 127.9, 127.7, 127.2, 126.9, 126.1, 123.0, 47.6, 31.1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C23H21ClN3 374.1419; Found 374.1418.
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5-Benzyl-N-(tert-butyl)-1-(4-methoxyphenyl)-1H-imidazol-2-amine (7k). Light yellow solid (yield 0.476 g,
71%), mp 108ꢀ110 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.16ꢀ6.87 (m, 9H), 6.56 (s, 1H), 3.83 (s, 3H),
3.60 (s, 2H), 3.26 (s, 1H), 1.33 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 159.5, 148.5, 138.8, 129.5,
128.5, 128.0, 127.6, 126.1, 125.9, 122.5, 114.7, 55.4, 51.7, 31.0, 29.6. HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C21H26N3O 336.2070; Found 336.2077.
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N-Butyl-5-(4-methylbenzyl)-1-phenyl-1H-imidazol-2-amine (7l). Light yellow solid (yield 0.447 g, 70%),
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mp 74ꢀ76 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.40ꢀ7.07 (m, 5H), 6.96 (d, J = 7.2 Hz, 2H, ArꢀH),
6.83 (d, J = 7.2 Hz, 2H), 6.53 (s, 1H), 3.59 (s, 2H), 3.38 (t, J = 5.4 Hz, 1H), 3.31ꢀ3.28 (m, 2H), 2.27 (s,
3H), 1.52ꢀ1.47 (m, 2H), 1.33ꢀ1.27 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm)
149.8, 135.5, 135.4, 135.1, 129.7, 128.7, 128.6, 128.3, 128.1, 126.7, 122.6, 43.3, 32.0, 30.5, 21.0, 20.1,
13.8. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C21H26N3 320.2121; Found 320.2142.
5-(4-Chlorobenzyl)-N-isopropyl-1-(p-tolyl)-1H-imidazol-2-amine (7m). Light yellow oil (yield 0.469 g,
69%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.20 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.91 (d, J =
7.8 Hz, 2H), 6.87 (d, J = 7.8 Hz, 2H), 6.54 (s, 1H), 3.96ꢀ3.91 (m, 1H), 3.58 (s, 2H), 3.22 (d, J = 7.8 Hz,
1H), 2.39 (s, 3H), 1.14 (d, J = 6.0 Hz, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 149.4, 138.8, 137.2,
132.1, 131.6, 130.3, 129.7, 128.0, 127.7, 125.7, 122.7, 44.9, 30.3, 23.3, 21.1. HRMS (ESIꢀTOF) m/z: [M
+ H]+ Calcd for C20H23ClN3 340.1575; Found 340.1595.
5-Benzyl-4-methyl-1-phenyl-N,N-dipropyl-1H-imidazol-2-amine (7n). Light yellow oil (yield 0.556 g,
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80%); H NMR (CDCl3, 600 MHz) δ (ppm) 7.28ꢀ6.96 (m, 8H), 6.85 (d, J = 7.8 Hz, 2H), 3.66 (s, 2H),
2.84 (t, J = 7.2 Hz, 4H), 2.23 (s, 3H), 1.36ꢀ1.30 (m, 4H), 0.67 (t, J = 7.2 Hz, 6H); 13C NMR (CDCl3, 150
MHz) δ (ppm) 151.2, 139.6, 137.1, 130.5, 128.7, 128.1, 128.0, 127.8, 127.7, 125.7, 122.6, 53.7, 29.5, 20.8,
12.8, 11.3. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C23H30N3 348.2434; Found 348.2463.
1-(5-Benzyl-1-(2-chlorophenyl)-4-methyl-1H-imidazol-2-yl)piperidine (7o). Light yellow oil (yield 0.519
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g, 71%); H NMR (CDCl3, 600 MHz) δ (ppm) 7.39 (d, J = 7.8 Hz, 1H), 7.25ꢀ7.04 (m, 5H), 6.91 (d, J =
7.8 Hz, 1H), 6.78 (d, J = 6.6 Hz, 2H), 3.76 (d, J = 16.8 Hz, 1H), 3.52 (d, J = 16.8 Hz, 1H), 2.92 (t, J = 5.4
Hz, 4H), 2.24 (s, 3H), 1.38ꢀ1.32 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 152.1, 139.2, 134.9,
133.2, 130.7, 130.6, 130.1, 129.4, 128.0, 127.9, 127.1, 125.8, 123.1, 51.0, 29.8, 25.6, 24.1, 12.9. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C22H25ClN3 366.1732; Found 366.1728.
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5-Benzyl-4-ethyl-N,N-dipropyl-1-(p-tolyl)-1H-imidazol-2-amine (7p). Light yellow oil (yield 0.556 g,
74%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.06ꢀ6.97 (m, 5H), 6.78ꢀ6.74 (m, 4H), 3.58 (s, 2H), 2.75 (t, J
= 7.2 Hz, 4H), 2.47 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.26ꢀ1.12 (m, 4H), 0.60 (t, J = 7.2 Hz, 6H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 151.3, 139.9, 137.3, 136.6, 134.5, 129.2, 127.9, 127.8, 127.6, 125.6,
121.6, 53.8, 29.4, 20.9, 20.8, 20.5, 14.9, 11.3. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C25H34N3
376.2747; Found 376.2764.
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1-(5-Benzyl-1-butyl-1H-imidazol-2-yl)piperidine (7q). Light yellow oil (yield 0.363 g, 61%); H NMR
(CDCl3, 600 MHz) δ (ppm) 7.27ꢀ7.17 (m, 5H), 6.54 (s, 1H), 3.86 (s, 2H), 3.60 (t, J = 7.2 Hz, 2H), 2.95 (t,
J = 6.6 Hz, 4H), 1.64ꢀ1.21 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 153.4,
138.3, 128.3, 128.2, 127.1, 126.3, 123.8, 52.7, 42.4, 32.0, 31.2, 26.0, 23.9, 19.7, 13.5. HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C19H27N3Na 320.2097; Found 320.2072.
1-(1-Isopropyl-5-(4-methylbenzyl)-1H-imidazol-2-yl)piperidine (7r). Light yellow solid (yield 0.351 g,
59%), mp 60ꢀ62 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.09ꢀ7.04 (m, 4H), 6.48 (s, 1H), 4.35ꢀ4.30 (m,
1H), 3.86 (s, 2H), 2.93 (t, J = 6.0 Hz, 4H), 2.31 (s, 3H), 1.66ꢀ1.56 (m, 6H), 1.34 (d, J = 6.6 Hz, 6H); 13
C
NMR (CDCl3, 150 MHz) δ (ppm) 153.4, 135.7, 135.4, 128.9, 128.2, 127.2, 124.6, 53.3, 46.5, 31.3, 26.0,
23.9, 21.8, 20.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C19H28N3 298.2278; Found 298.2256.
N-Benzyl-5-(4-chlorobenzyl)-1-isopropyl-N-methyl-1H-imidazol-2-amine (7s). Light yellow oil (yield
0.439 g, 62%); 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.33ꢀ7.24 (m, 7H), 7.08 (d, J = 7.8 Hz, 2H), 6.48 (s,
1H), 4.60ꢀ4.55 (m, 1H), 4.11 (s, 2H), 3.90 (s, 2H), 2.64 (s, 3H), 1.27 (d, J = 6.6 Hz, 6H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 153.0, 138.1, 137.1, 132.1, 129.8, 128.7, 128.4, 128.2, 127.1, 126.6, 125.4,
60.8, 46.4, 42.2, 31.4, 21.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C21H25ClN3 354.1732; Found
354.1731.
Acknowledgements
We gratefully acknowledge financial support of this work by the National Natural Science Foundation of
China (No. 21572075) and the 111 Project B17019.
Supporting Information
1H and 13C NMR spectra of compounds 7aꢀ7s. This material is available free of charge via the Internet at
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